While identification of tumor-specific target antigens has been a major hurdle to overcome for prevention of cancer progression by vaccination or immunotherapy, a second challenge has been the induction of immune responses to these “self” antigens. Tumor antigen-specific primary T cell responses must be induced from naïve T cells in the peripheral blood, or alternatively from primed, but anergic or tolerized T cells. The prospects for immunological treatment of cancer have risen sharply in recent years, based in part on the identification of dendritic cells (DC) as powerful professional antigen-presenting cells capable of inducing primary CD4+ helper T cell and CD8+ cytotoxic T lymphocyte (CTL) responses in vitro and in vivo. Clinical trials of DC vaccination have demonstrated induction of anti-tumor immune responses, and therapeutic benefit has been observed in a proportion of patients, but responses are inconsistent and it is clear that current approaches are not optimal (1).
In addition to the technical challenges of vaccination with ex vivo-generated DC, there is a burgeoning appreciation that tumor-associated CD4+ regulatory T cells (Treg) represent a major barrier to effective DC vaccination and other forms of active or passive cellular immunotherapy (2-4). The clinical significance of tumor-associated CD4+ Treg was highlighted by the work of Curiel and colleagues, who showed that Treg are recruited to ovarian tumors by the chemokine CCL22 (predominantly expressed by ovarian tumors), and that the presence of Treg confers immune privilege and is associated with a poor prognosis and increased mortality (5). These observations are underlined by further studies showing that high expression of the forkhead box transcription factor P3 (Foxp3), which is preferentially expressed by CD4+ Treg, is an independent prognostic factor for reduced overall survival in ovarian cancer (6). Such findings lend credence to the notion that strategies for depletion of tumor-associated Treg, or inhibition of Treg function, may be of therapeutic benefit, particularly in conjunction with active, tumor-specific immunotherapy. Indeed, a recent clinical trial of tumor RNA-transfected DC vaccination combined with denileukin diftitox (a fusion protein of IL-2 and diphtheria toxin, which targets CD25 preferentially expressed by CD4+ Treg) for patients with renal cell carcinoma resulted in reduced numbers of Treg in the peripheral blood and enhanced generation of tumor-specific T cell responses (7).
While there is an increasing consensus that active immunotherapy or antitumor vaccination should be supported by selective and efficient depletion of Treg, there is also a new appreciation that vaccination itself may induce or expand Treg, thus promoting tumor-specific tolerance. Vaccination with recombinant vaccinia virus in a mouse tumor model system resulted in expansion of both effector and regulatory T cells, with Treg function being dominant, blocking effector function in vitro and in vivo (8). In a notable clinical study, injection of DC matured with inflammatory cytokines (TNFα, IL-1β, IL-6 and PGE2) expanded foxp3+CD4+ Treg in 3 of 3 myeloma patients tested (9). While it is well known that immature DC induce Treg and peripheral tolerance (10-12), the finding that mature DC can also expand Treg has come as an unpleasant surprise, and has serious implications for current approaches to DC vaccination. From these observations, it is apparent that although depletion of Treg prior to vaccination may be necessary, Treg depletion alone will not be sufficient for optimal post-vaccine effector function and antitumor immunity. Redirection of DC-driven maturation and function will also be required to prevent de novo induction of vaccine antigen-specific Treg.
Improved treatments for cancer are needed, including improved methods of vaccinating to induce a patient's own immune system to attack his cancer. Improved methods of vaccinating to prevent cancer are also needed. Improved vaccination methods to treat or prevent other diseases are also needed.